Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF-X
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Beatrix Ueberheide
PROVIDER: MSV000086571 | MassIVE | Wed Dec 09 13:44:00 GMT 2020
REPOSITORIES: MassIVE
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Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.
2022-05-27 | PXD032030 | Pride
Project description:Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY-E10) were incubated, with or without Hsp90 inhibitors. Experiment Overall Design: Three ATL cell lines(TaY-E10, MT-2, and MT-4) were cultured in the presence or absence of Hsp90 inhibitors(17-AAG and 17-DMAG).
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